Cav2.1 (P/Q-type) channels are the primary presynaptic calcium channels in glutamatergic neurons in the CNS, and Ca2+ entry through these channels initiates neurotransmitter release. Because neurotransmitter release is dependent on the third or fourth power of calcium, regulation of Cav2.1 channels will have profound effects on synaptic transmission. Recent work has identified differential regulation of Cav2.1 channels by calmodulin (CaM) and several members of a family of related neuro-specific Ca2+-binding proteins (nCaBPs). Expression of CaM and nCaBPs in synapses determines the type of regulation these channels undergo. For example, CaM causes Ca2+-dependent facilitation and Ca2+-dependent inactivation while the nCaBP, Ca2+-binding protein 1, causes Ca2+-independent inactivation. The research proposed here will determine the molecular mechanisms for this divergent regulation and ask how Ca2+-dependent facilitation and inactivation of presynaptic Cav2.1 channels contributes to the regulation of synaptic transmission and short-term synaptic plasticity. This work will elucidate important signaling mechanisms contributing to short-term synaptic plasticity, which plays an important role in tuning network properties. [unreadable] [unreadable]